Abstract
Inactivation of the tumor suppressor gene p53 is commonly observed in human prostate cancer and is associated with therapeutic resistance. We have previously demonstrated that green tea polyphenols (GTP) induce apoptosis in prostate cancer cells irrespective of p53 status. However, the molecular mechanisms underlying these observations remain elusive. Here we investigated the mechanisms of GTP-induced apoptosis in human prostate cancer LNCaP cells stably-transfected with short hairpin-RNA against p53 (LNCaPshp53) and control vector (LNCaPshV). GTP treatment induced p53 stabilization and activation of downstream targets p21/waf1 and Bax in a dose-dependent manner specifically in LNCaPshV cells. However, GTP-induced FAS upregulation through activation of c-jun-N-terminal kinase resulted in FADD phosphorylation, caspase-8 activation and truncation of BID, leading to apoptosis in both LNCaPshV and LNCaPshp53 cells. In parallel, treatment of cells with GTP resulted in inhibition of survival pathway, mediated by Akt deactivation and loss of BAD phosphorylation more prominently in LNCaPshp53 cells. These distinct routes of cell death converged to a common pathway, leading to loss of mitochondrial transmembrane potential, cytochrome c release and activation of terminal caspases, resulting in PARP-cleavage. GTP-induced apoptosis was attenuated with JNK inhibitor, SP600125 in both cell lines; whereas PI3K-Akt inhibitor, LY294002 resulted in increased cell death prominently in LNCaPshp53 cells, establishing the role of two distinct pathways of GTP-mediated apoptosis. Furthermore, GTP exposure resulted in inhibition of class I HDAC protein, accumulation of acetylated histone-H3 in total cellular chromatin, resulting in increased accessibility of transcription factors to bind with the promoter sequences of p21/waf1 and Bax, regardless of the p53 status of cells, consistent with effects elicited by an HDAC inhibitor, trichostatin A. These results demonstrate that GTP induces prostate cancer cell death by two distinct mechanisms regardless of p53 status, thus identifying specific well-defined molecular mechanisms that may be targeted by chemopreventive and/or therapeutic strategies.
Highlights
With limited treatment options available for prostate cancer, patients with relapsing disease are treated with anti-androgens
Similar effects of lower magnitude were observed in LNCaPshV cells (Figure 3 D&E). These results demonstrate that the magnitude of cell death caused by green tea polyphenols (GTP) exposure is similar in both cell lines, the pathways that lead to apoptosis are different and might be influenced by p53 status
We recently demonstrated that GTP suppresses class I histone deacetylases (HDACs) in human prostate cancer cells [13], and the present study provides additional confirmation that GTP acts as an HDAC inhibitor
Summary
With limited treatment options available for prostate cancer, patients with relapsing disease are treated with anti-androgens. It is well established that cancer cells may acquire chemoresistance through a variety of mechanisms, most of them implying an altered apoptotic program [2]. Recent studies have demonstrated that p53 status might be a critical determinant for chemo-sensitivity in human tumors [3,4]. More than 50% of human cancers, including prostate cancer, exhibit loss of normal p53 functions and/or defects in the p53 signaling pathway as well as missense mutations or deletions; these molecular alterations are associated with resistance to cell death [4,5]. The relative ineffectiveness of current chemotherapeutic regimens justifies a continued search for safe and effective agents that might improve treatment and/or inhibit the development of resistance to chemotherapy
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